title: Human cytomegalovirus is protected from inactivation by reversible binding to villous trophoblasts.
abstract: Human cytomegalovirus (HCMV) is the leading cause of congenital disease in the developed world. Transmission of HCMV to the fetus can occur through the villous placenta. Previously, we have shown that although syncytiotrophoblast (ST) can be productively infected, it is more likely that HCMV reaches the fetus through breaks in the ST than through basal release of progeny virus from infected ST. Progeny virus released on the maternal side could interact back with the ST and accumulate. In pregnancy, the organ distribution of disease burden is dramatically shifted, with the placenta reported as a reservoir for some pathogens. Thus, we propose that the ST layer functions as a viral reservoir, where HCMV is harbored and ultimately protected from degradation. Using primary cytotrophoblasts differentiated into an ST culture in vitro and challenged with HCMV, we have defined reversible binding between the virus and trophoblasts that protects the virus from degradation. This is blocked by treatment with low pH and neutralizing intravenous immunoglobulin. This reversible binding likely is to heparan sulfate proteoglycans, because heparin treatment blocks it. Importantly, we show that bound and released virus maintained in culture for at least 48 h results from inoculum and not progeny virus. Thus, the placenta has the potential to accumulate a relatively high steady-state level of virus within the intervillous space resulting from localized binding and release at the ST. A better understanding of the molecular interactions between HCMV and ST will provide insights regarding interventions to prevent or minimize congenital transmission.
authors.affiliation: Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Ashley
authors.initials: A
authors.lastname: Davey
authors.forename: Lauren
authors.initials: L
authors.lastname: Eastman
authors.forename: Priyanka
authors.initials: P
authors.lastname: Hansraj
authors.forename: Denise G
authors.initials: DG
authors.lastname: Hemmings
mesh_terms: D057134:Antibodies, Neutralizing; D018938:Caco-2 Cells; D003587:Cytomegalovirus / Q000276:immunology / Q000378:metabolism*; D003586:Cytomegalovirus Infections / Q000151:congenital / Q000635:transmission; D005260:Female; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006493:Heparin; D054884:Host-Pathogen Interactions; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016756:Immunoglobulins, Intravenous; D018445:Infectious Disease Transmission, Vertical; D011247:Pregnancy; D014327:Trophoblasts / Q000378:metabolism / Q000821:virology*; D053585:Virus Attachment; D038301:Virus Inactivation
chemical_list: D057134:Antibodies, Neutralizing; D019812:Heparan Sulfate Proteoglycans; D016756:Immunoglobulins, Intravenous; D006493:Heparin